Malaria causes 400,000 children deaths and 200,000 unborn infant deaths per year. We lack an effective malaria vaccine partially because we do not fully understand the mechanism of antibody mediated protection. Antibodies are predominantly thought to be effective through blocking mechanisms, and all the blood stage malaria vaccines centered on this mechanism have failed. However, we hypothesize that protective antibodies in Plasmodium infection ?tag? infected RBC surface proteins for recognition and killing by Fc receptor+ cells. We have data showing that NK cells inhibit the growth of Plasmodium in vitro through antibody dependent cellular cytotoxicity (ADCC). We went on to show that a subset of NK cells, ? neg NK cells, have enhanced ADCC function and abundance of ? neg NK cells correlates with reduced parasitemia and protection from malaria in a large endemic malaria cohort. We also have preliminary data showing that mice that lack Fc ? receptors do not clear parasites in vivo as well as wildtype mice. This proposal aims to use novel humanized and Fc ? receptor models to determine the contribution of NK cells and other innate cells to parasite clearance through ADCC and antibody dependent cellular phagocytosis (ADCP) in vivo. These results will help to understand how antibodies clear parasites in vivo, which will aid vaccine development because the antigens that Fc receptor/antibody bind will be different than antibody targets for blocking/neutralization mechanisms. This work will also set the foundation for additional follow-up studies.